NLRP3 inflammasome as a novel target for docosahexaenoic acid metabolites to abrogate glomerular injury

Guangbi Li, Zhida Chen, Owais M. Bhat, Qinghua Zhang, Justine M. Abais-Battad, Sabena M. Conley, Joseph K. Ritter, Pin Lan Li

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

The nucleotide-binding oligomerization domainlike receptor containing pyrin domain 3 (NLRP3) inflammasome has been implicated in podocyte injury and glomerular sclerosis during hyperhomocysteinemia (hHcys). However, it remains unclear whether the NLRP3 inflammasome can be a therapeutic target for treatment of hHcys-induced kidney injury. Given that DHA metabolites-resolvins have potent antiinflammatory effects, the present study tested whether the prototype, resolvin D1 (RvD1), and 17S-hydroxy DHA (17S-HDHA), an intermediate product, abrogate hHcys-induced podocyte injury by targeting the NLRP3 inflammasome. In vitro, confocal microscopy demonstrated that 17S-HDHA (100 nM) and RvD1 (60 nM) prevented Hcys-induced formation of NLRP3 inflammasomes, as shown by reduced colocalization of NLRP3 with apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) or caspase-1. Both DHA metabolites inhibited Hcys-induced caspase-1 activation and interleukin-1β production. However, DHA had no significant effect on these Hcys-induced changes in podocytes. In vivo, DHA lipoxygenase metabolites substantially inhibited podocyte NLRP3 inflammasome formation and activation and consequent glomerular sclerosis in mice with hHcys. Mechanistically, RvD1 and 17S-HDHA were shown to suppress Hcys-induced formation of lipid raft redox signaling platforms and subsequent O2 production in podocytes. It is concluded that inhibition of NLRP3 inflammasome activation is one of the important mechanisms mediating the beneficial action of RvD1 and 17S-HDHA on Hcys-induced podocyte injury and glomerular sclerosis.

Original languageEnglish (US)
Pages (from-to)1080-1090
Number of pages11
JournalJournal of Lipid Research
Volume58
Issue number6
DOIs
StatePublished - Jun 2017
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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